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Chromosome structure deficiencies in MCPH1 syndrome

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Abstract

Mutations in the MCPH1 gene result in primary microcephaly in combination with a unique cellular phenotype of defective chromosome condensation. MCPH1 patient cells display premature chromosome condensation in G2 phase of the cell cycle and delayed decondensation in early G1 phase, observable as an increased proportion of cells with prophase-like appearance. MCPH1 deficiency thus appears to uncouple the chromosome cycle from the coordinated series of events that take place during mitosis such as some phases of the centrosome cycle and nuclear envelope breakdown. Here, we provide a further characterization of the effects of MCPH1 loss-of-function on chromosome morphology. In comparison to healthy controls, chromosomes of MCPH1 patients are shorter and display a pronounced coiling of their central chromatid axes. In addition, a substantial fraction of metaphase chromosomes shows apparently unresolved chromatids with twisted appearance. The patient chromosomes also showed signs of defective centromeric cohesion, which become more apparent and pronounced after harsh hypotonic conditions. Taking together, the observed alterations indicate additional so far unknown functions of MCPH1 during chromosome shaping and dynamics.

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Acknowledgments

We are indebted to the patients, their parents and the clinicians for their cooperation. We thank S. Niehage for her excellent technical assistance in some analyses. Technical and human support provided by CICT of Universidad de Jaén (UJA, MINECO, Junta de Andalucía, FEDER) is gratefully acknowledged.

Conflict of interest

The authors declare no conflict of interest.

Ethical approval

All procedures were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Funding

This work was supported by Universidad de Jaén (grant UJA2011/12/36), Junta de Andalucía (Funding program “Ayudas a grupos de investigación”, reference BIO220) and by Deutsche Forschungsgemeinschaft (grant NE531/5-3).

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Authors and Affiliations

  1. Department of Experimental Biology, University of Jaén, Paraje Las Lagunillas s/n, E-23071, Jaén, Spain

    M. Arroyo, A. Sánchez & J.A. Marchal

  2. Institute of Medical Genetics and Human Genetics, Charite Virchow-Klinikum Hospital, Berlin, Germany

    M. Trimborn & H. Neitzel

  3. Chromosome Dynamics Laboratory, RIKEN, Wako, Saitama, Japan

    T. Hirano

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  1. M. Arroyo
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  2. M. Trimborn
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  3. A. Sánchez
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  4. T. Hirano
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  6. J.A. Marchal
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Correspondence to J.A. Marchal.

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Arroyo, M., Trimborn, M., Sánchez, A. et al. Chromosome structure deficiencies in MCPH1 syndrome. Chromosoma 124, 491–501 (2015). https://doi.org/10.1007/s00412-015-0512-2

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